NM_001460.5:c.1588delT

Variant names:

• chr1-171209118-CT-C
• rs2234889
• NM_001460.5:c.1588delT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001460.5(FMO2):​c.1588delT​(p.Cys530AlafsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 527,618 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: FMO2 NM_001460.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 0 publications found

Genes affected

FMO2 (HGNC:3770): (flavin containing dimethylaniline monoxygenase 2) This gene encodes a flavin-containing monooxygenase family member. It is an NADPH-dependent enzyme that catalyzes the N-oxidation of some primary alkylamines through an N-hydroxylamine intermediate. However, some human populations contain an allele (FMO2*2A) with a premature stop codon, resulting in a protein that is C-terminally-truncated, has no catalytic activity, and is likely degraded rapidly. This gene is found in a cluster with other related family members on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

ENSG00000225243 (HGNC:):

ENSG00000231424 (HGNC:40240):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001460.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO2	NM_001460.5	MANE Select	c.1588delT	p.Cys530AlafsTer23	frameshift	Exon 9 of 9	NP_001451.2
	FMO2	NM_001365900.2		c.1393delT	p.Cys465AlafsTer23	frameshift	Exon 8 of 8	NP_001352829.1
	FMO2	NM_001301347.2		c.928delT	p.Cys310AlafsTer23	frameshift	Exon 7 of 7	NP_001288276.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO2	ENST00000209929.10	TSL:1 MANE Select	c.1588delT	p.Cys530AlafsTer23	frameshift	Exon 9 of 9	ENSP00000209929.8
	FMO2	ENST00000488431.1	TSL:2	n.580delT		non_coding_transcript_exon	Exon 2 of 2
	FMO2	ENST00000529935.5	TSL:2	n.*911delT		non_coding_transcript_exon	Exon 7 of 7	ENSP00000487002.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000246 AC: 13 AN: 527618 Hom.: 0 Cov.: 7 AF XY: 0.0000218 AC XY: 6 AN XY: 275314

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000735 AC: 1 AN: 13598

American (AMR) AF: 0.0000554 AC: 1 AN: 18058

Ashkenazi Jewish (ASJ) AF: 0.0000724 AC: 1 AN: 13814

East Asian (EAS) AF: 0.00 AC: 0 AN: 30804

South Asian (SAS) AF: 0.0000472 AC: 2 AN: 42334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2100

European-Non Finnish (NFE) AF: 0.0000232 AC: 8 AN: 345472

Other (OTH) AF: 0.00 AC: 0 AN: 28434

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2234889; hg19: chr1-171178257; COSMIC: COSV108026265;